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Insulin signaling in Drosophila melanogaster mediates A? toxicity.

ABSTRACT: Alzheimer's disease (AD) and diabetes are clinically positively correlated. However, the connection between them is not clarified. Here, using Drosophila as a model system, we show that reducing insulin signaling can effectively suppress the toxicity from A? (Amyloid beta 42) expression. On the other hand, A? accumulation led to the elevation of fly insulin-like peptides (ILPs) and activation of insulin signaling in the brain. Mechanistically, these observations are attributed to a reciprocal competition between Drosophila insulin-like peptides and A? for the activity of insulin-degrading enzyme (IDE). Intriguingly, peripheral insulin signaling is decreased despite its heightened activity in the brain. While many upstream factors may modify A? toxicity, our results suggest that insulin signaling is the main downstream executor of A? damage, and thus may serve as a promising target for Alzheimer's treatment in non-diabetes patients. This study explains why more Alzheimer's cases are found in diabetes patients.

SUBMITTER: Huang Y

PROVIDER: S-EPMC6325060 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Insulin signaling in <i>Drosophila melanogaster</i> mediates Aβ toxicity.

Huang Yunpeng Y Wan Zhihui Z Wang Zhiqing Z Zhou Bing B

Communications biology 20190108

Alzheimer's disease (AD) and diabetes are clinically positively correlated. However, the connection between them is not clarified. Here, using <i>Drosophila</i> as a model system, we show that reducing insulin signaling can effectively suppress the toxicity from Aβ (Amyloid beta 42) expression. On the other hand, Aβ accumulation led to the elevation of fly insulin-like peptides (ILPs) and activation of insulin signaling in the brain. Mechanistically, these observations are attributed to a recipr ...[more]

PMID: 30652125

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Project description:Graphical abstract Highlights • Contact to Dithiothreitol (DTT), a widely used antioxidant, is lethal to the fruit fly Drosophila melanogaster.• At low concentrations, DTT contact induces the expression of some apoptosis genes.• In parallel, DTT triggers the expression of a cuticle barrier gene.• Expression of some genes involved in detoxification is intensified with increasing DTT concentrations.• Toxicity of DTT to the exnvironment should be tested. The thiol-containing compound Dithiothreitol (DTT) has been shown to be toxic to cultured cells by inducing the generation of reactive oxygen species that ultimately cause cell death. However, its effects on multicellular organisms and the environment have not been investigated yet in detail. In this work, we tested the toxicity of DTT to the model insect Drosophila melanogaster. We show that DTT is lethal to D. melanogaster by topical application but not through feeding. DTT treatment triggers the transcription of the canonical apoptosis regulators grim, hid and rpr at low amounts. The amplitude of this induction declines with elevating DTT amounts. By live microscopy, we observe apoptotic cells especially in the gut of DTT treated flies. In parallel, low DTT amounts also activate the expression of the cuticle barrier component gene snsl. This indicates that a physical defence response is launched upon DTT contact. This combined measure is seemingly successful in preventing fly death. The expression of a number of known detoxification genes including cyp6a2, cyp6a8, cyp12d1 and GstD2 is also enhanced through DTT contact. The degree of upregulation of these genes is proportional to the applied DTT amounts. Despite this effort, flies exposed to high amounts of DTT eventually die. Together, D. melanogaster is able to sense DTT toxicity and adjust the defence response successfully at least at low concentrations. This is the first time to analyse the molecular consequences of DTT exposure in a multicellular organism. Our work provides a new model to discuss the physiological response of animals against thiol toxins and to resurvey the effect of redox agents on the environment.

Project description:BackgroundSexual-size dimorphism (SSD) is replete among animals, but while the selective pressures that drive the evolution of SSD have been well studied, the developmental mechanisms upon which these pressures act are poorly understood. Ours and others' research has shown that SSD in D. melanogaster reflects elevated levels of nutritional plasticity in females versus males, such that SSD increases with dietary intake and body size, a phenomenon called sex-specific plasticity (SSP). Additional data indicate that while body size in both sexes responds to variation in protein level, only female body size is sensitive to variation in carbohydrate level. Here, we explore whether these difference in sensitivity at the morphological level are reflected by differences in how the insulin/IGF-signaling (IIS) and TOR-signaling pathways respond to changes in carbohydrates and proteins in females versus males, using a nutritional geometry approach.ResultsThe IIS-regulated transcripts of 4E-BP and InR most strongly correlated with body size in females and males, respectively, but neither responded to carbohydrate level and so could not explain the sex-specific response to body size to dietary carbohydrate. Transcripts regulated by TOR-signaling did, however, respond to dietary carbohydrate in a sex-specific manner. In females, expression of dILP5 positively correlated with body size, while expression of dILP2,3 and 8, was elevated on diets with a low concentration of both carbohydrate and protein. In contrast, we detected lower levels of dILP2 and 5 protein in the brains of females fed on low concentration diets. We could not detect any effect of diet on dILP expression in males.ConclusionAlthough females and males show sex-specific transcriptional responses to changes in protein and carbohydrate, the patterns of expression do not support a simple model of the regulation of body-size SSP by either insulin- or TOR-signaling. The data also indicate a complex relationship between carbohydrate and protein level, dILP expression and dILP peptide levels in the brain. In general, diet quality and sex both affect the transcriptional response to changes in diet quantity, and so should be considered in future studies that explore the effect of nutrition on body size.

Dataset Information

Insulin signaling in Drosophila melanogaster mediates A? toxicity.

Publications

Insulin signaling in <i>Drosophila melanogaster</i> mediates Aβ toxicity.

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